Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[C:26]1[CH:31]=CC=C[CH:27]=1.NC1C=CC(CN/C=C2\C(=O)NC(=O)C3C\2=CC(I)=CC=3)=CC=1O[Si](C(C)C)(C(C)C)C(C)C.C(Cl)(=O)CC>>[OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9]/[CH:10]=[C:11]2\[C:12](=[O:23])[NH:13][C:14](=[O:22])[C:15]3[C:20]\2=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]=1[NH:24][C:25](=[O:32])[CH:26]([CH3:27])[CH3:31]
Reactant: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Agent: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Agent: CCC(=O)Cl
Product: CC(C)C(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (75 mg, 0.13 mmol) is reacted with propionyl chloride (110 μL, 1.3 mmol). Following desilylation and precipitation, N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]-2-methylpropanamide is obtained (9.3 mg, 15%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cn2ccnc2c(NCc2ccncc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cccc(-c2cn3ccnc3c(NCc3ccncc3)n2)c1
Temperature: 25 °C

Procedure:
A mixture of (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-pyridin-4-ylmethyl-amine 4 (1.0 equiv.), 3-aminophenyl boronic acid (1.1 equiv.), Pd (PPh3)4 (0.10 equiv.), and K3PO4 (2.20 equiv.) in 4:1 1,4-dioxane:water is heated to 90° C. for 24 hr. The mixture is cooled to RT and partitioned between EtOAc and sat. NaHCO3. The aqueous phase is extracted with EtOAc and combined extracts are dried over Na2SO4. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (EtOAc) to yield [6-(3-Amino-phenyl)-imidazo[1,2-a]pyrazin-8-yl]-pyridin-4-ylmethyl-amine 5.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[CH2:31]([C:38]([OH:40])=O)[CH2:32][C:33]1[N:37]=[CH:36][NH:35][CH:34]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]([CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=1)[C:50]([N:52]1[CH2:55][C:54]([O:63][CH2:64][CH2:65][CH2:66][CH3:67])([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53]1)=[O:51]>CN(C)C=O>[CH2:64]([O:63][C:54]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][N:52]([C:50](=[O:51])[C@H:49]([NH:48][C:38](=[O:40])[CH2:31][CH2:32][C:33]2[N:37]=[CH:36][NH:35][CH:34]=2)[CH2:68][C:69]2[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=2)[CH2:55]1)[CH2:65][CH2:66][CH3:67]
Reactant: O=C(O)CCc1c[nH]cn1
Reactant: CCCCOC1(c2ccccc2F)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC1(c2ccccc2F)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
81 mg (0.3 mmol) of TBTU and 0.1 ml (0.6 mmol) of triethylamine are added to a solution of 42 mg (0.25 mmol) of desamino-histidine hydrochloride in 1 ml of dimethylformamide. After stirring for 10 minutes, 119 mg (0.2 mmol) of (R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxyphenyl)propan-1-one trifluoroacetate are added and the reaction medium is stirred for 64 h at ambient temperature. After extraction with a 1/2 heptane/ethyl acetate mixture, the organic phase is washed with 1N aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with a 90/10 dichloromethane/methanol mixture. 59 mg of N—[(R)-2-[3-butoxy-3-(2-fluoro-phenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white solid with a yield of 57%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:12][C:13]3[C:22]([CH:23]=2)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=3)[CH:7]=[CH:8][CH:9]=1.C[Si](C)(C)[Cl:30].O>CC(C)=O>[ClH:30].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:23]3[C:22](=[N:21][C:20]4[C:15]([CH:14]=3)=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:13][CH2:12][C:11]=2[CH2:24][N:25]([CH3:26])[CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(C2=Cc3nc4ccccc4cc3CC2CN(C)C)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(C2=C(CN(C)C)CCc3nc4ccccc4cc32)c1
Yield: 22.9 %

Procedure:
18 g of the product from Step 1 were dissolved in 200 ml methanol under dry nitrogen. The reaction mixture was treated with 7.7 g 2-aminobenzaldehyde as the hydrochloride and was subsequently heated to 80° C. After adding 400 ml 1 N hydrochloric acid, the reaction solution was stirred for eight days at 80° C. After cooling to room temperature, the reaction mixture was diluted with 200 ml ethyl acetate and was made alkaline with concentrated sodium hydroxide solution while being cooled in ice. The aqueous phase was extracted three times with 100 ml portions of ethyl acetate each time, and the combined organic phases were dried over magnesium sulfate and evaporated to dryness under vacuum. The residue was eluted and purified by column chromatography on silica gel using ethyl acetate/methanol in a ratio of 4/1. The first product fraction contained 5.4 g [3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethylamine base in the form of beige crystals. In order to prepare the hydrochloride, the solid was dissolved with heating in 200 ml acetone and was treated with trimethylchlorosilane and water in equimolar amounts. 5.2 g (28.3% theoretical) [3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethyl-amine hydrochloride were obtained (light yellow crystals, m.p.: 201° C. to 204° C.). 4.4 g [1-(3-methoxy-phenyl)-3,4-dihydro-acridin-2-yl-methyl]-dimethylamine base in the form of a beige, amorphous solid was obtained as the second fraction. To release the hydrochloride, the solid was dissolved with heating in 200 ml acetone and was treated with trimethylchlorosilane and water in equimolar amounts. 4.2 g (22.90% theoretical) [1-(3-methoxy-phenyl)-3,4-di-hydro-acridin-2-yl-methyl]-dimethylamine hydrochloride were obtained in the form of light yellow crystals, m.p.: 195° C. to 198° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]([CH:16]=O)([CH3:15])[CH3:14].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH:16]([NH:11][C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]([CH3:14])([CH3:15])[CH3:12])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: CC(C)(C)C=O
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)CCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)CCc1ccccc1)n1nnc2ccccc21

Procedure:
A suspension of 3-phenyl-propionamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as described in Example 1C to provide the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].C([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:29](=[O:37])[C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:7][CH:5]([O:4][C:2]([N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:29]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([Cl:36])[CH:31]=2)=[O:37])[CH2:19][CH2:20]1)=[O:3])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: O=C(Nc1ccc(Cl)cc1C1=CCN(Cc2ccccc2)CC1)c1ccnc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(Cl)OC(=O)N1CC=C(c2cc(Cl)ccc2NC(=O)c2ccnc(Cl)c2)CC1

Procedure:
1-Chloroethyl chloroformate (2.64 ml) was added to a suspension of N-[2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-chloro-phenyl]-2-chloro-isonicotinamide (530 mg) in toluene (30 ml). After 15 min. the solution was heated to reflux for 16 hours, then poured into saturated aqueous NaHCO3 solution and the mixture extracted three times with CH2Cl2. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford the crude title product (550 mg).
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:13][CH2:14][P:15]([CH2:20][N:21]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:19])[O:16][CH2:17][CH3:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CCCCCC.C1COCC1.CCOCC>[C:29]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:21][CH2:20][P:15]([CH:14]([N:13]=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:19])[O:16][CH2:17][CH3:18])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)CN=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOP(=O)(CN=C(c1ccccc1)c1ccccc1)C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78 %

Procedure:
A 1.53 N butyllithium solution (0.3 ml; 0.46 mmol) in hexane is added dropwise to a stirred solution of the ethyl phosphinate 3 (200 mg; 0.42 mmol) in THF (10 ml) at -78° C. under an atmosphere of argon. After 5 minutes benzyl bromide (0.06 ml; 0.51 mmol) is added dropwise to the deep-red reaction solution. After 2 hours the reaction solution is warmed to room temperature and after 15 hours diluted with ether. The solution is extracted with saturated aqueous ammonium chloride solution (2×20 ml). The organic phase is dried over Na2SO4 and evaporated under reduced pressure. The monoalkylated phosphinate 4 (187 mg, 79% of theory) is obtained after purification on silica gel using column chromatography (ethyl acetate/heptane=2/3).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][CH:6]2[S:10][CH:11]=[C:12]([C:13]3[CH:25]=[CH:24][C:16]([CH:17]=[N:18][O:19][CH2:20][C:21]([OH:23])=O)=[CH:15][CH:14]=3)[CH:5]2[C:4]=1[OH:26])#[N:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.C(O)C(N)(CO)CO>ClCCl.CN(C)C(=O)C>[C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]2[S:10][CH:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16](/[CH:17]=[N:18]/[O:19][CH2:20][C:21]([NH:34][CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[O:23])=[CH:24][CH:25]=3)[C:5]=2[C:4]=1[OH:26])#[N:2]
Reactant: NCc1ccccn1
Reactant: N#CC1=C(O)C2C(c3ccc(C=NOCC(=O)O)cc3)=CSC2NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(O)c2c(-c3ccc(/C=N/OCC(=O)NCc4ccccn4)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(5-Cyano-4-hydroxy-6-oxo-3a,6,7,7a-tetrahydro-thieno[2,3-b]pyridin-3-yl)-benzylideneaminooxy]-acetic acid (0.035 g, 0.1 mmol) and C-pyridin-2-yl-methylamine (0.013 g, 0.12 mmol) were added to a suspension of resin bound 1,3-dicyclohexyl carbodiimide (0.166 g, 1.2 mmol/g, 0.2 mmol) and 1-hydroxybenzotriazole hydrate (0.013 g, 0.1 mmol) in 1:1 dichloromethane/N,N-dimethylacetamide (4 mL) at room temperature. After complete reaction, resin bound trisamine (4.7 mmol/g, 0.053 g, 0.25 mmol) was added to the reaction mixture, shaken at room temperature for 1 hour, filtered, concentrated and purified by RP-HPLC to afford the title compound. MS (ESI) m/e 457.8 (M−H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 12.15 (br s, 1H), 8.52–8.56 (m, 2H), 8.42 (s, 1H), 7.88 (dt, J=10.5, 1H), 7.61 (d, J=10, 2H), 7.51 (d, J=10, 2H), 7.38–7.43 (m 2H), 7.01 (s, 1H), 4.65 (s, 2H), 4.50 (d, J=5, 1H).
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[N:16]([CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:15]=2[CH2:37][CH2:38][NH2:39])[CH3:11])=[CH:6][CH:5]=1.[C:41]1([CH2:47][S:48](Cl)(=[O:50])=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH:24]([N:16]1[C:17]2[C:22](=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]([CH2:13][CH2:12][N:10]([CH3:11])[C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:40])=[CH:9][CH:8]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:48]([CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:50])=[O:49])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COC(=O)c1ccc(N(C)CCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: CN(CCc1c(CCNS(=O)(=O)Cc2ccccc2)n(C(c2ccccc2)c2ccccc2)c2ccc(Cl)cc12)c1ccc(C(=O)O)cc1
Yield: 83 %

Procedure:
The intermediate from step 7 was treated with α-toluenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 83% yield.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH:39][CH2:40][C@H:41]([OH:50])[C@@H:42]([OH:49])[C@H:43]([OH:48])[C@H:44]([OH:47])[CH2:45][OH:46]>>[CH3:38][N:39]([CH2:40][C@H:41]([OH:50])[C@@H:42]([OH:49])[C@H:43]([OH:48])[C@H:44]([OH:47])[CH2:45][OH:46])[C:32]([N:12]1[C@@:13]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)([CH3:24])[C@@:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([CH3:16])[N:15]=[C:11]1[C:8]1[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[O:35][CH2:36][CH3:37])=[O:33]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (2R,3R,4R,5S)-6-methylamino-hexane-1,2,3,4,5-pentaol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H47Cl2N4O7 [(M+H)+] 717.2817, observed 717.2813.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Al+3].[Cl-].[Cl-].[Cl-].C([Zn]CC)C.[C:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:24][CH3:25])([CH3:23])[CH3:22]>>[C:21]([C:26]1[CH:27]=[CH:28][C:29]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:30][CH:31]=1)([CH2:24][CH3:25])([CH3:22])[CH3:23]
Reactant: CCC(C)(C)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: CC[Zn]CC
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)(C)c1ccc(C(=O)c2ccccc2C(=O)O)cc1
Yield: 79.8 %

Procedure:
74 g (0.5 mole) of phthalic anhydride were reacted with 128 g (1.05 moles) of AlCl3 and 25 g (0.2 mole) of diethylzinc in 74 g of tert-amylbenzene, similarly to Example 1. After the mixture had been worked up, 118 g (80% of theory) of pure 2-(4'-tert-amylbenzoyl)-benzoic acid were obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39]([NH2:41])=[S:40])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[NH:38][C:39]([NH:41][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:40])([CH3:30])[CH3:29]
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: Cc1ccc(NC(N)=S)c(C(C)C)c1
Product: Cc1ccc(NC(=S)NC(=O)NCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C(C)C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-isopropyl-4-methylphenyl)thiourea isolated as a white solid (0.077 g, 25%): 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 10.10 (s, 1H), 9.42 (s, 1H), 8.15-8.05 (m, 2H), 8.04-7.96 (m, 2H), 7.61 (ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.16-7.11 (m, 1H), 7.05-6.96 (m, 2H), 3.46 (q, J=6.7 Hz, 2H), 2.91 (dt, J=17.9, 6.9 Hz, 3H), 2.30 (s, 3H), 1.14 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][Cl:27].O>CN(C=O)C.C(OCC)(=O)C>[Cl:27][CH2:26][CH2:25][CH2:24][N:7]1[C:8]2[C:13](=[CH:12][C:11]([CH2:15][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[CH:10][CH:9]=2)[CH:14]=[C:6]1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc2cc(Cn3ccnc3)ccc2[nH]1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(Cn3ccnc3)ccc2n1CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Ethoxycarbonyl-5-(1H-imidazol-1-ylmethyl)-1H-indole (1.00 g) was dissolved in DMF (10 ml), and thereto was added sodium hydride (156 mg, purity 60%) under ice-cooling, followed by stirring at room temperature for 1 hour. Thereto was added 1-bromo-3-chloropropane (0.39 ml ), and the mixture was stirred for 1.5 hours. 1-Bromo-3-chloropropane (0.20 ml) was added again, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture for extraction, followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (Daisogel 15 g, elution; CHCl3 --CHCl3 /MeOH=50/1-30/1) to give 1.26 g of an oily substance (1). IR (Neat, νcm-1) 1710, 1700, 1520, 1470 1H-NMR (CDCl3, δ ppm) 1.40 (3H, t, J=6.6 Hz, CH2CH3 ), 2.29 (2H, m, CH2CH2Cl), 3.63 (2H, t, J=6.0 Hz, CH2Cl), 4.38 (2H, quart, J=6.6 Hz, CH2CH3), 4.72 (2H, t, J=6.0 Hz, NCH2), 5.20 (2H, s, C5--CH2), 6.70-7.85 (7H, indole H, imidazole H)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:32][CH2:33][N:34]([C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=4)[N:16]=3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(C2(O)CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
DIPEA (1.174 mL, 6.74 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (1 g, 4.49 mmol) and 4-(4-hydroxyphenyl)piperidin-4-ol (0.955 g, 4.94 mmol) in DMF (10 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. The residues were triturated with water and the resulting solid collected by filtration, washed with further water followed by ether, then dried under vacuum to afford 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (1.680 g, 99%) as a solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cccc2c1CNCC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2cccc(O)c2C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an-ice cooled suspension of 8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (746 mg, 5.0 mmol, 1.0 eq.) and triethylamine (2.13 mL, 15.0 mmol, 3.0 eq.) in DCM (25 mL), benzyl chloroformate (0.83 mL, 5.5 mmol, 1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (50 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (20 mL) and 1M aq. NaOH soln. (6 mL) was added. The mixture was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×25 ml). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by CC (SiO2, Hept/AcOEt 8:2 to 7:3) to give the title compound as a white solid.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([OH:31])=O)[C@H:25]([CH2:27][CH3:28])[CH3:26].O.[NH:40]1[CH2:54][CH2:53][CH2:52][C@@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([N:40]1[CH2:54][CH2:53][CH2:52][C@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])=[O:31])[C@H:25]([CH2:27][CH3:28])[CH3:26]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 85 %

Procedure:
While cooling on ice, DCC (1.24 g, 6.0 mmol) and triethylamine (0.70 ml, 4.0 mmol) were added to DMF (10 ml) containing Boc-L-Ile-OH.1/2 H2O (1.39 g, 6.0 mmol), H-D-Pro-OBzl-HCl (956 mg, 4.0 mmol), and HOBt.H2O (613 mg, 4.0 mmol). After stirring for 8 hours, DMF was removed by evaporation, the residue was dissolved in ethyl acetate, and then successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. After drying over MgSO4 and concentrating, the resulting oily substance was purified by flash silica gel chromatography (4×30 cm, 1% methanol/chloroform). to obtain the oily title compound (1.63 g, 3.38 mmol, 85% yield). TLC: Rf=(CHCl3/MeOH=9/1)